Subarachnoid hemorrhage (SAH), resulting from intracerebral bleeding or from trauma, is a serious neurologic event. Frequent complications of SAH include cerebral infarction (stroke), cerebral edema with increased intracranial pressure, and death.
If a patient survives the initial insult of SAH, a further complication is that of cerebral vasospasm. Cerebral vasospasm is a syndrome that accompanies SAH and generally has peak clinical manifestations at 7-10 days following SAH. The syndrome is characterized by diffuse narrowing of cerebral arteries in the general region of the hemorrhage. Clinically, this arterial narrowing is correlated with the amount of blood that is present in the subarachnoid space. The arterial narrowing can become sufficiently severe that blood flow to previously undamaged brain is compromised, resulting in risk of subsequent stroke without adequate treatment.
Current treatment for vasospasm includes increasing systemic blood pressure and expanding the intravascular space, both of which are correlated clinically with improving symptoms of cerebral ischemia in vasospasm. This therapy necessitates an intensive care unit setting, is not universally successful, and can lead to complications in some patients.
Despite several decades of research, no clear etiology for vasospasm has been elucidated. Multiple general approaches have been taken, including investigation of vasoconstrictors, cytokines, and other pro-inflammatory modulators. None of these putative agents, however, has emerged as clearly causative in the syndrome of vasospasm.
Histologic analyses of cerebral vessels suffering from vasospasm has revealed evidence of vascular cell and adventitial cell proliferation at times of peak arterial narrowing. Vascular cell proliferation is often attributable to locally high concentrations of relevant mitogenic agents, such as growth factors. Intriguingly, blood that is outside the vascular space, such as blood in the subarachnoid space, spontaneously forms clots with concomitant platelet activation. Platelets are known to be repositories of several growth factors, including platelet-derived growth factors, that are potent mitogens for cells in the vascular wall.
The present invention results from the realization that the narrowing of cerebral arteries that is characteristic of cerebral vasospasm is in fact due to proliferation of cells in the vascular wall and/or accumulation of extracellular matrix under the influence of growth factors.
The extracellular matrix contains cross-linked collagen and elastin fibers. Collagen and elastin fibers in the extracellular matrix of blood vessels bear the tensile load in response to pressure from blood flow within the blood vessel. After their synthesis, collagen molecules are processed in the Golgi and endoplasmic recticulum. 4-Prolyl hydroxylase (PH) is the enzyme responsible for hydroxylating residues in collagen molecules (Kivirikko et al, Matrix Biology 16:357 (1998)). This modification permits collagen molecules to associate strongly in small helical fibers. Following production of helically-wound collagen fibers, collagen is excreted from the cell into the extracellular space, where it can be strengthened by spontaneously forming larger fibers (“fibrils”) and by being cross-linked. Lysyl oxidase (LO) is the enzyme primarily responsible for cross-linking collagen and elastin fibers once these molecules have been secreted into the extracellular space. (Rucker et al, Am. J. Clin. Nutr. 67(suppl.):9965 (1998).) Collagen fibrils are substantially strengthened with the addition of cross-links between and within fibers that restrict movement of the fibers under tension.
The present invention provides a method of treating or preventing cerebral vasospasm by inhibiting vascular proliferation and/or extracellular matrix synthesis, secretion or strengthening (e.g., collagen fiber formation and self-assembly, as well as molecular cross-linking).